Various factors may cause skin lesions such as wounds, decubitus ulcer or thermal ulcer. Such skin lesions causing considerable patients' distress has been realized also as a pharmacoeconomically serious problem, because it often requires a long-term treatment to repair the skin lesion especially in case of chronic skin lesions such as decubitus ulcer.
The skin lesion healing is accomplished, in general, through a serial events comprising (1) inflammation phase, (2) cell-proliferation phase and (3) epidermis/corium-reconstitution phase. It is considered that various factors such as a platelet-derived growth factor (PDGF), a basic fibroblast growth factor (bFGF), a vascular endothelial cell growth factor (VEGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF) and the like work under highly complicated relationships in the healing process. From a histopathological aspect, transient angiogenesis is an essential event in the process of skin lesion healing. In this regard, among the growth factors mentioned above, VEGF is one of primary promoting factors of angiogenesis and promote the skin lesion healing (American Journal of Pathology (2004): Vol. 164(6), pp 1935-47, FASEB Journal (2004): Vol. 18(11), pp 1264-66).
As an agent for the treatment of skin lesion, a prostaglandin E2 preparation (alprostadil alphadex), dibutyryl cAMP preparation (bucladecin sodium), a sucrose/povidone iodide preparation, a tretinoin tocoferyl preparation and the like has been known. These agents, however, are not always efficient in treatment of chronic skin lesions such as chronic skin ulcers.
Recently, bFGF, one of the growth factors mentioned above, was developed owing to its physiological activity (angiogenesis-promoting activity) based on fibroblast-, vascular endothelial cell- and vascular smooth muscle cell-proliferation promoting activity and coming into practical use.
There are some other medicaments which may be used as an agent for promoting the skin lesion healing. For example, some literatures report that a prostaglandin I1, (PGI1) derivative showed a promoting activity on wound healing in animal models (Japanese Journal of Pharmacology (1995): Vol. 67 (Suppl. I), p 275 (P3-116)) or that a phosphodiesterase 5 inhibitor such as syldenafil being clinically used for treatment of electile dysfunction may be expected to promote wound healing due to its vasodilating activity mediated by increase in intracellular cGMP level (WO2002/015893). However, these drugs are not coming into practical use yet.
On the other hand, there are some literatures to report that a certain kind of compounds, for example, an oxygen-containing heterocyclic compound such as a benzofuran compound (U.S. Pat. No. 6,716,987) or a nicotinic acid compound (US Patent Publication No. 2003/0195233) may be expected to show wound healing-promoting effect. However, neither their mechanism of action in wound healing process nor clinical usefulness remains to be proved.
Meanwhile, a pyridine compound (i.e., a pyridyl-substituted naphthalene compound and a pyridyl-substituted isoquinoline compound), which is an active ingredient of the present invention, has been known as an anti-asthma agent having a bronchoconstriction-inhibitory activity and airway inflammation-inhibitory activity mediated by its PDE4-inhibitory activity (EP748805, EP848000). But their skin lesion healing-promoting activity has never been reported.